Summary Impact Type

Research Subject Area(s)

Download original

Summary of the impact

Clare Stanford's group has opened up a new line of research for drug
treatment of Attention Deficit Hyperactivity Disorder. Based on this work,
UCL Business has been awarded an EU patent for the NK1R `knockout' mouse
as an investigative tool and pharmaceutical screen. Cerebricon, a
subsidiary of Charles River, has taken an exclusive licence to market this
mouse and advertise it on their website. Our studies have also enabled us
to identify a new genetic locus in which abnormalities are linked to ADHD
in humans, and to identify a new drug candidate for treating ADHD.

Underpinning research

The core diagnostic features of Attention Deficit Hyperactivity Disorder
(ADHD) are hyperactivity, inattentiveness and impulsivity.
All current drug treatments for ADHD augment monoamine transmission in the
brain. First-choice treatments are the psychostimulants d-amphetamine and
methylphenidate, despite being ineffective in nearly 30% of patients.

Several rat and mouse inbred strains have been used in preclinical
studies of ADHD. All express one or more of the abnormalities seen in
ADHD, which are relieved by psychostimulants to some extent. However, none
matches all key characteristics of ADHD and its treatment.

Our experiments with the substance P-preferring (NK1) receptor knockout
(NK1R-/-) mouse, in collaboration with Professor Stephen Hunt (UCL),
started in 2004. We aimed to explain why blocking the activation of NK1R
has antidepressant effects in humans, as was thought to be the case at the
time. In the course of this work, we discovered that NK1R-/- mice have
profound abnormalities in monoamine transmission in the brain. As well as
an increase in serotonin release, which had been reported already, we
found increased noradrenaline release and a striking deficit in dopamine
release in the prefrontal cortex. The latter change is inconsistent with
an antidepressant profile. We also noted that NK1R-/-mice are hyperactive
compared with wildtypes [1]. This hyperactivity is induced by
either genetic mutation (NK1R-/-) or pharmacological antagonism of NK1R
and so is a direct consequence of a lack of functional NK1R. Moreover, it
was prevented by treatment with d-amphetamine or methylphenidate, as in
ADHD [3].

These findings led us to propose that neurochemical and behavioural
abnormalities, arising from a lack of functional NK1R, could underlie
abnormalities seen in ADHD. This prompted a human genetic study, in
collaboration with Professor Hugh Gurling (UCL), which found a strong
association between four genetic markers in the tacr1 gene (the
human equivalent of the NK1R gene) and ADHD in a large population sample [4].
Since then, polymorphism(s) of the tacr1 gene have also been found
to be associated with bipolar affective disorder, suicidal behaviour and
alcoholism, all of which show a high incidence of co-morbidity with ADHD.

In an MRC-funded project (2008-11), we showed that NK1R-/- mice display a
higher behavioural inattentiveness, impulsivity, and perseveration
(which has been reported in ADHD patients) and that d-amphetamine relieved
perseveration but not inattentiveness or impulsivity[5]. This pattern of deficits in cognitive performance and their
response to amphetamine is consistent with the abnormalities in monoamine
transmission in the NK1R-/- mouse, and could explain why some ADHD
patients do not respond to psychostimulants.

All these findings strengthen the validity of using NK1R-/- mice to study
underlying causes of, and treatments for, ADHD. They also underpin our
prediction that drugs that augment activation of NK1R, or its downstream
targets, would have beneficial effects in ADHD, particularly in patients
with polymorphism(s) of the tacr1 gene.

Finally, we have recently uncovered a potential role for nifedipine, a
drug already in use as an antianginal and antihypertensive, in the
treatment of ADHD, through its effect on L-type calcium channels [6].

Details of the impact

Attention Deficit Hyperactivity Disorder has a worldwide prevalence in
children of about 5% and persists in adulthood in 50-60% of cases. ADHD is
not a primary learning disorder but its core diagnostic features are
deficits in cognitive performance and response control [`hyperactivity',
`inattentiveness' and `impulsivity']. These impairments
disrupt academic development and can lead to complex social problems in
adulthood. The majority of adult patients further experience serious
co-morbidity including: perseveration, substance misuse, emotional
lability, bipolar disorder, criminality and suicidality, all of which
impair the quality of life of the patient and their family and can reduce
life-expectancy. An unexplained increased risk of other medical conditions
(e.g. obesity, asthma) as well as accidents and social problems leads to
ADHD patients costing 2-fold more than the average patient (NICE, 2009).
It was predicted that about £78 million would be spent on pharmacotherapy
alone for ADHD patients in the UK in 2012 (NICE, 2009). This figure did
not take into account the broader economic costs of this illness.

Only three drugs are licensed to treat ADHD in the UK: the
psychostimulants d-amphetamine & methylphenidate, and the
noradrenaline uptake inhibitor atomoxetine. There is widespread unease
about long-term use of psychostimulants, and all these treatments can have
harmful cardiovascular side-effects and carry a risk of misuse.
Furthermore, more than 25% of patients do not respond to any of these
treatments. Thus, there is a pressing need for a new approach to
pharmacotherapy of ADHD, based on a strong scientific rationale.

New ADHD Animal Model: Commercial Impact

Our research has led to the discovery that disruption of NK1 receptor
function causes deficits in cognitive performance and response control
similar to those seen in ADHD patients. This research has opened up new
directions for investigation of the underlying causes of ADHD as well as
the discovery and development of new drug targets. A paper describing some
of our recent findings has received more than 2,700 hits since it was
published in May 2011. This research has already received MRC funding of
more than £600,000 [a].

We were awarded an EU patent in 2010 relating to the use of the NK1R-/-
mouse to investigate the underlying neurochemical abnormalities in ADHD
and as a screen for putative drug treatments for ADHD [b]. We have
a US patent application pending [c]. A subsidiary of Charles
River, Cerebricon (based in Finland), which specializes in validation and
marketing of rodent behavioural models, has negotiated an exclusive
licence with UCL Business [d]. This enables them to market the
NK1R-/-for use in research related to the causes and treatment of ADHD and
now advertise this on their website. This venture is expected to be highly
successful: "In conjunction with Cerebricon's strategy of increasing
our portfolio of pre-clinical models by extending from neurology to
psychiatry we are very pleased to have the opportunity to in-license
what we believe will prove to be the best and most fully validated mouse
model of ADHD for our drug development clientele" — Dr Yrjanheikki,
CEO of Cerebricon [e].

New Genetic Locus for ADHD in Humans: Health Impact

Our research using the NK1R KO mice led us to discover a link between the
mutations in the human homologue of the gene, tacr1, and ADHD.
This discovery is significant to clinical psychiatry at two levels. One is
that new treatments targeted at specific individuals, according to the
genetic subtype of the disorder that they have inherited, can now be
attempted. Secondly, the findings identify a molecular pathophysiology
which cuts across traditional diagnostic boundaries and indicates that the
use of biomarkers which identify genetic effects acting in sub categories
of mental illness will be more powerful and useful than traditional
clinical diagnostic categories [f].

Public Engagement

Because of ADHD's often disruptive nature, sufferers can face difficulty
in public situations. Increasing public understanding of the disorder is
therefore extremely important. Clare Stanford makes regular media
appearances to discuss psychopharmacology in general [g], and has
written an article on ADHD, which is aimed at the general public and
posted on the website (Information for the Public) hosted by the British
Association for Psychopharmacology [h].

The development of new treatments for almost all human diseases and
disorders requires animal research. However, this can be a contentious
issue. Clare Stanford is President of the Laboratory Animal Science
Association and has contributed to meetings that aim to increase public
understanding of animal research (e.g. meetings for the RSPCA) [i].

[c] Stanford SC et al. Patent Number 20100169994 [USA] PCT NO:
PCT/GB08/00160371 Date: February 15, 2010 The invention relates to the use
of a NK1-/- animal as a model for attention deficit hyperactivity disorder
and related conditions, to markers for those conditions and to methods of
treating such conditions. http://www.google.com/patents/US20100169994

[d] Details can be verified by Business Manager, UCLB. Contact details
provided.